Regulation of Protein Translation Initiation by Estrogen

Abstract

Translational control of gene expression is critical for cellular homeostasis. We focus on eukaryotic initiation factor 3 (eIF3), a large translation initiation factor complex composed of 13 subunits (eIF3a‐eIF3m) in human cells. Overexpression of several eIF3 subunits (eIF3a, b, c, h, i, and m) or underexpression of two eIF3 subunits (eIF3e and f) are observed in a variety of malignancies, including breast, prostate, lung, cervical, and gastric cancers.Estrogens are key hormones regulating the development and function of reproductive organs in all vertebrates, including puberty onset, fertility, and the estrous cycle. Estrogens also play important roles in many non‐reproductive functions in mediating cardiovascular function, bone metabolism, embryonic and fetal brain development, and other critical biological processes. Estrogen signaling is critical for the development and progression of several types of cancer. Estrogen receptor(ER)a is a nuclear transcription factor that upon binding to its ligand estrogen can promote expression of growth and survival genes, and inhibit expression of transcriptional repressors, antiproliferative and proapoptotic genes.We hypothesized that in addition its transcriptional role, estrogen‐ERa signaling acts to regulate protein synthesis. We observed that ERa regulates both eIF3 levels and activity, and therefore rearranges the translational machinery to promote the synthesis of specific factors involved in malignant transformation. Our results indicate there exists regulation of eIF3 transcription by ERa. Moreover, estrogen controls the ERa/eIF3 interaction, subsequently directing the assembly of translation initiation complexes and mRNA translation.In conclusion, estrogen may act as a master regulator of gene expression. In addition to its genomic activity in control of transcription, non‐genomic estrogen signaling regulates protein synthesis, and leads to increased levels of proteins that mediate estrogenic functions.Support or Funding InformationCA151112‐02, RSG‐13‐287‐01TBEThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.